4-(dimethylaminoethylamino)-6-methoxy quinoline and salts thereof



United States Patent 4-(DIMETHYLAMINOE'I'HYLAMINO)-6-METHOXY QUlNOLlNEAND SALTS THEREOF Charles F. Geschickter, Kensington, and Leonard M.Rice, Baltimore, Md.

No Drawing. Application June 7, 1955,

Serial No. 513,906

3 Claims. (Cl. 260286) The present invention relates to new quinolinederivatives, to non-toxic salts thereof, and to methods of making thesecompounds. More particularly our invention relates to a4-dimethylaminoethylamino-6-methoxy quinoline and to non-toxic saltsthereof which We have found to be effective remedies for asthma andrelated allergic disorders.

This application is a continuation-in-part of application Serial No.378,420 filed September 3, 1953, which is a continuation-in-part ofapplication Serial No. 251,980 filed October 18, 1951. It is also acontinuation of applications Serial No. 378,422, filed September 3,1953, and Serial No. 446,946 filed July 30, 1954, and acontinuation-in-part of Serial No. 379,781, filed December 11, 1953.

We have found that 4-dimethylaminoethylamino-6- methoxy quinoline hasbronchial dilator and antihistaminic action and that it tends toconcentrate in the respiratory tissues. For this reason, the compound iseffective in the treatment of asthma. While this base compound isinsoluble in water it may be administered orally in oil solutions and wehave found that it has a cumulative effect and is characterized by longretention in the body.

Non-toxic salts of the base have the same bronchial dilator andantihistaminic action and have other desirable properties which makethem easier or more convenient to administer and improve the safetyfactor for administration. All of the non-toxic salts have the bronchialdilator and antihistaminic action but due to their other properties, thesalts fall into different groups.

The non-toxic inorganic salts such as the chloride, bromide, iodide,phosphate and sulphate are very soluble in water but they are acidic andpainful when administered by injection. Complex organic salts such asthe salts of phthalamic, quininic, nicotinic, and ascorbic acids andtheophylline are soluble, substantially neutral, have low toxicity andbecause of their relatively high molecular weights have a relativelyhigh safety factor. The non-toxic simple organic salts such as theacetate, tartarate, myristate and stearate have properties which are ingeneral between those of the inorganic salts and those of the complexorganic salts. The simple organic salts are generally less acidic thanthe inorganic salts and, as the molecular weight increases, they becomeless soluble in water and more soluble in oils.

An important object of the present invention is to provide as a novelcomposition of matter, 4-dimethylaminoethylamino, 6-methoxyquinoline andnon-toxic salts thereof.

Another object is to provide quinoline compounds which are a remedy forasthma and related allergic disorders.

Another object is to provide water-soluble, non-toxic quinolinecompounds.

Another object is to provide non-toxic quinoline compounds which aresubstantially neutral.

Another object is to provide non-toxic quinoline compounds which aresubstantially stable and moisture proof.

Another object is to provide methods of making4-dimethylaminoethylamino-6-methoxy quinoline and nontoxic saltsthereof.

The free base form of the compounds of the present invention is4-dimethylaminoethylamino-6-methoxyquinoline which has thefollowingformula:

This new quinoline derivative and its non-toxic salts have been testedin over 500 patients and have been found to be effective in thetreatment of asthma and related allergic disorders. The compounds havebeen found to have anticholine and antihistaminic effects and to beconcentrated in the lungs and respiratory tissues. Their characteristicsinclude long retention in the body and a cumulative effect so that whenused in the treatment of asthma, relief is prolonged and dosage may bereduced as the treatment progresses. Another important property of thenew compound and its salts is low toxicity and absence of undesirableside effects.

The free base may be prepared as follows:.

I .Alpha-carbethoxy-B-( p-anisidino) -acrylate A mixture of 0.4 mole ofp-anisidine and 0.4 mole of. ethoxymethylene malonic ester was heated atdeg. until no more bubbles of alcohol could be detected coming from themixture.

II.-3 carbethoxy-4-hydroxy-6-methoxyquinolineIII.-3-carboxy-4-hydroxy-6-methoxyquinoline The ester group was removedby boiling with 18% hydrochloric acid for one hour. The solution wasfiltered and the desired free acid crystallized as the filtrate cooled.Melting point 271 with gas evolution.

I V.4-hydr0xy-6-methoxyquinoline The acid from III above was heated in aWoods metal bath at 275 deg. until the evolution of carbon dioxideceased. The product was taken up in hot water (20 ml. per gram) andtreated with decolorizing charcoal. This hot mixture was filtered andthe product crystallized from the filtrate in the form of needles.Melting point 240243 deg. The product in solution gives a pink or redcolor with a drop of ferric chloride solution.

V.-1;-chl0r0-6-melhoxyquinoline The 4-hydroxy-6-methoxy quinoline wasrefluxed with phosphorus oxychloride for 4 hours. After cooling thereaction mixture was hydrolyzed by pouring onto cracked ice and theresulting aqueous suspension made alkaline with sodium hydroxide. Theinsoluble product was filtered, washed with water and dried. Meltingpoint 80-81 deg.

VI.4-(B-dimethylaminoethyl) -6-meth0xyquin0line 4-chloro-6-methoxyquinoline (0.205 mole) and B-dimethylaminoethylamine (0.200 mole) wereheated slowly in a bomb tube with a crystal of K. I. to to deg. for 4hours. The reaction mixture was transferred with the aid of a littledilute hydrochloric acid to 500 ml. of water. The solution was extractedwith a little ether and next was neutralized with sodium hydroxide untilstrongly basic. The basic solution was extracted twice with ether andthe extract was dried over magnesium sulfate and Theoretical 68. 54 7. 817.13 Found 68. 42 7. 65 17. 32

The free base may be administered orally inan alcohol or oil solution.It is absorbed. into the system and ultimately concentrates in the lungsand bronchial tissues. In this form, absorption is slow but sincetheeffects are cumulative, the free base isefiective in relieving asthma.

The non-toxic organic and inorganic salts are as elfective as: the basecompound and generally have the additional desirable property of beingmore soluble, and hence, more convenient to administer; Non-toxicinorganic salts include the chloride, bromide, iodide, sulphate andphosphate and non-toxic organic salts include the acetate, citrate,tartarate, stearate, myristate, phythalate, naphtholate,succinateandzsalts of theophyllin, phthalamic acid, quininic acid, nicotinicacid, ascorbic acid and the like.

To prepare the inorganic salts, the appropriate acid in alcohol solutionis added to an alcohol solution. of the base. The salt is thenprecipitated with ether and recrystallized.v The hydrochloride forexample is a yellowish hydroscopic crystalline solid with an indefinitemelting point.. It is. soluble in alcohol and very soluble in water.

The inorganic salts have a high pH value and are painful whenadministered by injection. Neutralizing the pH value with a base mayprecipitate the free base. These salts are also hydroscopic so thathandling and storage presents a problem- The simple organic salts suchas the acetate, stearate, and myristate are prepared in a similarmanner. Analcohol solution of the chosen organic acid is added to analcohol solution of the base in molar proportions. The alcohol is thendistilled oif at reduced pressure.

The acetate is a. bull colored crystalline powder very soluble in waterand soluble in. alcohol, benzene, ether andoily vehicles. Ithas an.indefinite boilingpoint. T he. stearate is a yellowish oilinsoluble inwater but soluble. in common organic solvents. The myristate is an oiland issoluble in sesame: oil. and common organic solvents but not verysoluble inwater.

Some of these simple organic salts are very stable and moistureresistant. Because of this property they may be manufactured, shippedand stored. in bulk or tablet form without damageor deterioration.

The more complex organic salts such asthe salts of theophylline,quininic acid, phthalamic acid, nicotinic acid and ascorbic acid aresoluble, substantially neutral and often. havev a. lower toxicity thanthe basecompound. These salting radicals also have some bronchialdilator action so that these salts are more efiective and easier toadminister'than the base compound.

Because of. their relatively high molecular- Weights', the more complex:organic salts also have agreater factor of safety. The salting radicalhas substantially no toxicity: and variations in dosage will have arelatively minor'effect on the amount of basev compound administered.

Preparation of" thetheophylline salt of 6 meth0xy-4dimethylaminoethylamino quinoline A mixture of 29.6 grams oftheophylline' and 2415 like and injectedintramuscularly; A convenientsolution grams of 6 methoxy 4 (dimethylaminoethyl amino quinoline aredissolved in 200 ml. of dry acetone. The solution after filtering istransferred to a 3-liter container and the acetone is removed underreduced pressure. After most of the acetone has been removed, the lasttraces are removed under high vacuum. The residue is covered,redissolved in alcohol, from which it is obtained as a crystalline salt.

4-(dimezhylaminoethylamino)-6-methoxyquinoline,salt of quininic acid Amixture of 2.45 gr. of 4-dimethylaminoethylamino-6- methoxy quinolineand 4.06 gm. of quininic acid is heated at reflux with 35 cc. of dryacetone. Methanol (anhy drous) is added to the boiling solution untilthe material just dissolves. The solution is boiled an additionalseveral minutes and filtered. The solution is allowed to come to roomtemperature and diluted to permanent turibidity with anhydrous ether.Upon standing in the ice box for several hours there is obtained 5 gm;of the salt (77%)- in the form of needles which after filtration anddrying melts at 162-163; The salt dissolves inwater giving analmostneutral solution.

The N,N-diethyl sis-A tetrahydrophthalamate salt of 6-meth0xy-4(dimethylaminoethylamino) quinoline.

A mixture of 45.5 grams (0.2 mol) of N,N-diethyl cis-Atetrahydrophthalarnic acid and 25.5 grams (-0.1 mol.) of6-methoxy-4-(-dimethylaminoethylamino=) quin oline are dissolved in 200mli (a convenient quantity) of 'ry acetone. The solution, afterfiltering is-transferred to a container of suitable size and the acetoneremoved under reduced pressure. After most ofthe acetone has beenremoved the last traces are removed under high vacuum' (less than 0.1mm.). The residue is loosely powdered, transferred to amortar and finelypowdered. The product is an almost white, free flowing hygroscopicpowder.

In the process illustrated in the foregoing example, the following amicacids may be used in place of N,N-dietliyl' cis-M-tetrahydrophthalamicacid to obtain the" corresponding salts:

N,N-dimethyl phthalamic N,N-diethyl phthalamic N ,N-dimethylhexahydrophthalamic N,N diethyl hexahyd rophthalamic N,N-dimethyl cis-n-te trahydrophthamic Ascorbic acid salt of 4-(dimethylaminoethylamino)6- methoxy quinoline' To prepare this salt, 7.04 grams (O'.O4mole') ofascorbic acid dissolved in ml. of methanol was placed in a 500 ml. flaskfitted with a condenser. To this was-added 4.9 grams (0.08 mole) of4-(dimethylaminoethylamincr)= 6-methoxy quin'oline dissolved in 25' ml.of methanol.

The mixture was refluxed for onehour and the methanol distilled off in awater bath. The product was obtained as a yellow crystalline powder,very soluble and giving a neutral solution in Water.

The nicotinic acid salt was prepared in substantiallythe' same manner.

The complex organic salts such asthe phthal'amate,

ascorbate and the like may be administered orally or'by iniection. Fororal administration, the saltsare giverrin 50 mg. tablets or capsulesonce or twice" daily. For par== enteral administration, the salt may bedissolved in'wate'r, benzyl alcohol and dioctyl hexahydrophthalicestersolte tion', ora suitable oil such as'peanutoil, sesame oilor'theis 100 to 120 mg. per cc. and dosages of 36 cc. daily have been foundeffective and, since the results are cumulative, administration can bereduced to every other day or even weekly as indicated by the patientsresponse to the treatment. Since the 4-(dimethylaminoethylamino-dmethoxyquinoline is the primary active portion of the compound, dosages andconcentrations of the base compound and other salts are varied so thatsubstantially the same amount of the active portion is given.

From the foregoing it will be apparent that we are able to accomplishthe objects of our invention and provide novel compounds which havevaluable therapeutic properties and a process for producing suchcompounds. Various modifications can of course be made without departingfrom the spirit of the invention or the scope of the appended claims.The term acid addition salts used in the claims refers to salts of thetype formed by treating a base with an acid.

We claim:

1. As a new composition of matter the ascorbic acid No references cited.

3. A NOVEL COMPOSITION OF MATTER CONSISTING OF A COMPOUND SELECTED FROMTHE CLASS CONSISTING OF 4-(DIMETHYLAMINOETHYLAMINO)-6-METHOXY QUINOLINEAND NON-TOXIC, WATER SOLUBLE ACID ADDITION SALTS THEREOF.